Identification of a gene regulatory network associated with prion replication.
Identification of a gene regulatory network associated with prion replication.
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DOI：
10.15252/embj.201387150
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发表时间：
2014-07-17
期刊：
影响因子：
--
通讯作者：
Klöhn PC
中科院分区：
文献类型：
--
作者：
Marbiah MM;Harvey A;West BT;Louzolo A;Banerjee P;Alden J;Grigoriadis A;Hummerich H;Kan HM;Cai Y;Bloom GS;Jat P;Collinge J;Klöhn PC
PrPC是由细胞内的PrPC异常构象组成的聚集体。它们通过招募宿主编码的PrPC进行繁殖，尽管关键的相互作用蛋白和不同细胞系和群体的易感性差异的原因尚不清楚。我们得出了一组易感性明显不同的细胞系，这些细胞系无法用PrPC表达差异来解释，以确定这些因素。从高度敏感的细胞中分离出来的PrP抗性逆转株的转录组分析揭示了与敏感性相关的基因表达特征，并受到分化的调节。其中几个基因编码的蛋白质在细胞外基质(ECM)重塑中发挥作用，细胞外基质(ECM)是一种储存与疾病相关的PrP的隔室。沉默这些基因中的九个会显著增加易感性。沉默Paps2导致硫酸乙酰肝素过低，并增加了PrPC在ECM的沉积，同时增加了Prion的繁殖。此外，RGD肽抑制纤维连接蛋白1与整合素α8的结合抑制了金属蛋白酶-2/9，同时促进了Pron的增殖。综上所述，我们已经确定了一个基因调控网络，该网络与细胞外基质中的Prion传播相关，并受细胞分化状态的控制。
Prions consist of aggregates of abnormal conformers of the cellular prion protein (PrPC). They propagate by recruiting host-encoded PrPC although the critical interacting proteins and the reasons for the differences in susceptibility of distinct cell lines and populations are unknown. We derived a lineage of cell lines with markedly differing susceptibilities, unexplained by PrPC expression differences, to identify such factors. Transcriptome analysis of prion-resistant revertants, isolated from highly susceptible cells, revealed a gene expression signature associated with susceptibility and modulated by differentiation. Several of these genes encode proteins with a role in extracellular matrix (ECM) remodelling, a compartment in which disease-related PrP is deposited. Silencing nine of these genes significantly increased susceptibility. Silencing of Papss2 led to undersulphated heparan sulphate and increased PrPC deposition at the ECM, concomitantly with increased prion propagation. Moreover, inhibition of fibronectin 1 binding to integrin α8 by RGD peptide inhibited metalloproteinases (MMP)-2/9 whilst increasing prion propagation. In summary, we have identified a gene regulatory network associated with prion propagation at the ECM and governed by the cellular differentiation state.
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影响因子：
16.6
作者：
Freir, Darragh B.;Nicoll, Andrew J.;Klyubin, Igor;Panico, Silvia;Mc Donald, Jessica M.;Risse, Emmanuel;Asante, Emmanuel A.;Farrow, Mark A.;Sessions, Richard B.;Saibil, Helen R.;Clarke, Anthony R.;Rowan, Michael J.;Walsh, Dominic M.;Collinge, John
通讯作者：
Collinge, John
影响因子：
16.6
作者：
Goold, R.;Rabbanian, S.;Sutton, L.;Andre, R.;Arora, P.;Moonga, J.;Clarke, A. R.;Schiavo, G.;Jat, P.;Collinge, J.;Tabrizi, S. J.
通讯作者：
Tabrizi, S. J.
影响因子：
5.4
作者：
Bosque, PJ;Prusiner, SB
通讯作者：
Prusiner, SB
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
DOI：
10.1073/pnas.0308413101
发表时间：
2004-06-29
影响因子：
11.1
作者：
Fevrier, B;Vilette, D;Raposo, G
通讯作者：
Raposo, G